Superantigens, a Paradox of the Immune Response

Abstract

Staphylococcal enterotoxins are a wide family of bacterial exotoxins with the capacity to activate as much as 20% of the host T cells, which is why they were called superantigens. Superantigens (SAgs) can cause multiple diseases in humans and cattle, ranging from mild to life-threatening infections. Almost all S. aureus isolates encode at least one of these toxins, though there is no complete knowledge about how their production is triggered. One of the main problems with the available evidence for these toxins is that most studies have been conducted with a few superantigens; however, the resulting characteristics are attributed to the whole group. Although these toxins share homology and a two-domain structure organization, the similarity ratio varies from 20 to 89% among different SAgs, implying wide heterogeneity. Furthermore, every attempt to structurally classify these proteins has failed to answer differential biological functionalities. Taking these concerns into account, it might not be appropriate to extrapolate all the information that is currently available to every staphylococcal SAg. Here, we aimed to gather the available information about all staphylococcal SAgs, considering their functions and pathogenicity, their ability to interact with the immune system as well as their capacity to be used as immunotherapeutic agents, resembling the two faces of Dr. Jekyll and Mr. Hyde.

Keywords: enterotoxin; immunomodulation; molecular and cellular targets; staphylococcal superantigen; toxin pathogenicity.

Figure 1

Structural features of Staphylococcal superantigens. (A) Overall structure of staphylococcal enterotoxin G (SEG) PDB accession number 1XXG. The general structure of SEG is displayed as a cartoon, and the secondary structures are colored yellow, β strands; red, α helixes; and flexible loops, green. The N-terminal domain and the C-terminal extreme are both located in the same domain of the molecule. (B) Superimposition of SEG and SEB. SEG overall structure (red) was superimposed over SEB structure (green) with an RMS of 0.714 Å, suggesting high similarity. (C) Overall structure of TSST-1, showing a simpler general structure than that of other staphylococcal enterotoxins. All the figures were performed using the PyMOL software.

Figure 2

Structure of the SAg-HA-HLA DR1 complex. (A) Ribbon diagram of SEB-HA-HLA DR1 complex. (B) The interface of the interaction is shown in detail. SEB compromises residues in positions 43, 44, 45, 46, 47, 67, 89, 92, 94, 95, 115 and 209. HLA DR1α chain, involves the residues: 13, 17, 18, 36, 37, 39, 57, 60, 61, 63, 67 and 68. Non-contacts are found between the peptide and SEB or SEB with the DR1β chain. (C) Ribbon diagram of the SEI-HA-HLA DR1 complex. (D) The interface of the interaction is shown in detail. The interaction is coordinated by Zn²⁺. This metal ion interacts with His81 of the DR1β chain and His169, His207 and Asp209 of SEI. SEI compromises residues in positions 98, 100, 105 and 211 to contact the residues 307 and 309 of the hemagglutinin (HA). No contacts are found between SEI and the DR1α chain. In all panels, the superantigen is colored red; the HLAD1α chain, blue; and the DR1β chain, orange. Zn²⁺ is represented as a sphere in cyan and the HA peptide, green. The residues conforming the interaction surface are represented as balls and sticks and colored pink (SEB or SEI); cyan, HLAD1α chain; yellow, DR1β chain; and light green, HA peptide. The figures were performed using PyMOL and the analysis of the structures was carried out using the CCP4i suite program.

Figure 3

Crystallographic structures of the SAg-TCR interaction. (A) Ribbon diagram of SEG-mVβ8.2 complex. SEG is colored red and the TCR β chain, yellow (B) as shown in detail. SEG residues are colored pink and mVβ8.2 residues, wheat. Residues are indicated with a one letter code and numbered. (C) Ribbon diagram of the SEH–human TCR complex. SEH is colored red and the TCR, light blue (α chain) and yellow (β chain). (D) The interface of the interaction is shown in detail. SEH residues are colored hot pink, hVα27 chain residues are colored violet and hVβ19 residues are colored wheat. Residues are indicated with a one letter code and numbered. (E) Ribbon diagram of the SEH-TCR-MHC-II tri molecular complex. SEH is colored red, HLA-HA-DR1 is colored blue (α chain) and orange (β chain) and the TCR as indicated in C. (F) Superimposition of the SEI-HA-HLADR1 complex over the trimolecular complex using the DR1 as template. SEI shown in pink is clearly away from the interaction surface with the TCR α chain. The figures were performed using PyMOL and the analyses of the structures were carried out using the CCP4i suite program.